Glucose‐dependent insulinotropic polypeptide counteracts diet‐induced obesity along with reduced feeding, elevated plasma leptin and activation of leptin‐responsive and proopiomelanocortin neurons in the arcuate nucleus

Abstract Aim To clarify the effects of glucose‐dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. Materials and Methods Acute and subchronic effects of subcutaneous GIPFA‐085, a long‐acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet‐induced obese (DIO) mice and/or functional leptin‐deficient ob / ob mice. The effects of GIPFA‐085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca 2+ concentration ([Ca 2+ ] i ). Results Single bolus GIPFA‐085 (30, 300 nmol/kg) dose‐dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5‐6 hours and inhibited food intake at 2‐24 hours after injection in DIO mice. Daily GIPFA‐085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3‐12 of treatment in DIO, but not ob / ob , mice. GIPFA‐085 increased [Ca 2+ ] i in the ARC leptin‐responsive and proopiomelanocortin (POMC) neurons. GIPFA‐085 and leptin cooperated to increase [Ca 2+ ] i in ARC neurons and inhibit food intake. Conclusions GIPFA‐085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin‐responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes.